Tyrosine inactivation

In order for the cyclooxygenase to function, a source of hydroperoxide (R—O—O—H) appears to be required. The hydroperoxide oxidizes a heme prosthetic group at the peroxidase active site of PGH synthase. This in turn leads to the oxidation of a tyrosine residue producing a tyrosine radical which is apparendy involved in the abstraction of the 13-pro-(5)-hydrogen of AA (25). The cyclooxygenase is inactivated during catalysis by the nonproductive breakdown of an active enzyme intermediate. This suicide inactivation occurs, on average, every 1400 catalytic turnovers. 

Src tyrosine kinase contains both an SH2 and an SH3 domain linked to a tyrosine kinase unit with a structure similar to other protein kinases. The phosphorylated form of the kinase is inactivated by binding of a phosphoty-rosine in the C-terminal tail to its own SH2 domain. In addition the linker region between the SH2 domain and the kinase is bound in a polyproline II conformation to the SH3 domain. These interactions lock regions of the active site into a nonproductive conformation. Dephosphorylation or mutation of the C-terminal tyrosine abolishes this autoinactivation. 

Hamagnchi, M., Matsuyoshi, N., Ohnishi, Y., Goroh, B., Takeichi, M., and Nagai, Y (1993). p6()V Sic casucs tyrosine posphoryiation and inactivation of the N-cadhcrin-catenm ceii adhesion system. EMBO J. 12(1), 307-314. 

Isoflavones have been implicated in goiter induction. Soybean extracts inhibit reactions catalyzed by thyroid peroxidase (TPO), essential to the synthesis of thyroid hormones (Divi et al., 1997). Genistein and daidzein (at about 1-10 p,M of IC50) may act as alternative substrates for tyrosine iodination (Divi et al., 1997). Furthermore, genistein and daidzein have also been shown to cause the irreversible inactivation of TPO in the presence of hydrogen peroxide. Genistein also inhibits thyroxine synthesis in the presence of iodinated... 

Parker, L. L., and Piwnica-Worms, H. (1992). Inactivation of the p34cdc2 -cyclin B complex by the human WEE1 tyrosine kinase. Science 257 1955-1957. 

One of the principal rules of biochemical regulation is, When you turn something on, be sure that you have a way to turn if off. Signal transduction pathways are no different. Kinases are opposed by phosphatases. These enzymes simply hydrolyze the tyrosine or serine/threo-nine phosphate. Because they are in opposition, activation of the phosphatase (there are pathways for this too) is similar to inactivation of the opposing kinase. Often the two activities are coordinate regulated... 

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